Lysine Deacetylases Hda1 and Rpd3 Regulate Hsp90 Function thereby Governing Fungal Drug Resistance
نویسندگان
چکیده
The molecular chaperone Hsp90 is a hub of protein homeostasis and regulatory circuitry. Hsp90 function is regulated by posttranslational modifications including acetylation in mammals; however, whether this regulation is conserved remains unknown. In fungi, Hsp90 governs the evolution of drug resistance by stabilizing signal transducers. Here, we establish that pharmacological inhibition of lysine deacetylases (KDACs) blocks the emergence and maintenance of Hsp90-dependent resistance to the most widely deployed antifungals, the azoles, in the human fungal pathogen Candida albicans and the model yeast Saccharomyces cerevisiae. S. cerevisiae Hsp90 is acetylated on lysine 27 and 270, and key KDACs for drug resistance are Hda1 and Rpd3. Compromising KDACs alters stability and function of Hsp90 client proteins, including the drug-resistance regulator calcineurin. Thus, we establish acetylation as a mechanism of posttranslational control of Hsp90 function in fungi, functional redundancy between KDACs Hda1 and Rpd3, as well as a mechanism governing fungal drug resistance with broad therapeutic potential.
منابع مشابه
Regulation of Fungal Drug Resistance and Morphogenesis by Lysine Deacetylases
Hsp90 is a molecular chaperone that governs drug resistance, morphogenesis, and virulence in the leading human fungal pathogen Candida albicans. Previous work with Saccharomyces cerevisiae and C. albicans established acetylation as a novel mechanism of post-translational control of Hsp90 in fungi and implicated lysine deacetylases (KDACs) as key regulators of resistance to the most common class...
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